CN117430574B - Benzofuran derivative and preparation method and application thereof - Google Patents
Benzofuran derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN117430574B CN117430574B CN202311753674.4A CN202311753674A CN117430574B CN 117430574 B CN117430574 B CN 117430574B CN 202311753674 A CN202311753674 A CN 202311753674A CN 117430574 B CN117430574 B CN 117430574B
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- CN
- China
- Prior art keywords
- benzofuran
- chloro
- phenyl
- carboxamide
- trifluoromethyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 150000001907 coumarones Chemical class 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- -1 4-chloro-3- (trifluoromethyl) phenyl Chemical group 0.000 claims description 89
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- 238000006243 chemical reaction Methods 0.000 claims description 51
- 239000007787 solid Substances 0.000 claims description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 238000004440 column chromatography Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- HMZUPXGTBJYBSS-UHFFFAOYSA-N ethyl 4-bromo-1-benzofuran-2-carboxylate Chemical compound C1=CC=C2OC(C(=O)OCC)=CC2=C1Br HMZUPXGTBJYBSS-UHFFFAOYSA-N 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical compound C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 239000007821 HATU Substances 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- LQTXMBDCLHZDAM-UHFFFAOYSA-N 2-bromo-6-hydroxybenzaldehyde Chemical compound OC1=CC=CC(Br)=C1C=O LQTXMBDCLHZDAM-UHFFFAOYSA-N 0.000 claims description 6
- AWHJIEGQJDBVCF-UHFFFAOYSA-N 4-bromo-1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1Br AWHJIEGQJDBVCF-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 5
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- ASPDJZINBYYZRU-UHFFFAOYSA-N 5-amino-2-chlorobenzotrifluoride Chemical compound NC1=CC=C(Cl)C(C(F)(F)F)=C1 ASPDJZINBYYZRU-UHFFFAOYSA-N 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims description 3
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- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 abstract description 5
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- ZHROKKZCYDCXHE-UHFFFAOYSA-N tert-butyl 4-(2-ethoxycarbonyl-1-benzofuran-4-yl)piperazine-1-carboxylate Chemical compound C1=CC=C2OC(C(=O)OCC)=CC2=C1N1CCN(C(=O)OC(C)(C)C)CC1 ZHROKKZCYDCXHE-UHFFFAOYSA-N 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
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- 208000019425 cirrhosis of liver Diseases 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 6
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- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000003613 bile acid Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 4
- 208000006454 hepatitis Diseases 0.000 description 4
- XLGQSYUNOIJBNR-UHFFFAOYSA-N vonafexor Chemical compound C=1C=C2OC(C(=O)O)=CC2=C(Cl)C=1N(CC1)CCN1S(=O)(=O)C1=C(Cl)C=CC=C1Cl XLGQSYUNOIJBNR-UHFFFAOYSA-N 0.000 description 4
- WGGKQIKICKLWGN-UHFFFAOYSA-N 2,6-dichlorobenzenesulfonyl chloride Chemical compound ClC1=CC=CC(Cl)=C1S(Cl)(=O)=O WGGKQIKICKLWGN-UHFFFAOYSA-N 0.000 description 3
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- 238000012360 testing method Methods 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- MKARNSWMMBGSHX-UHFFFAOYSA-N 3,5-dimethylaniline Chemical compound CC1=CC(C)=CC(N)=C1 MKARNSWMMBGSHX-UHFFFAOYSA-N 0.000 description 2
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- 206010012735 Diarrhoea Diseases 0.000 description 2
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- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- IGRCWJPBLWGNPX-UHFFFAOYSA-N 3-(2-chlorophenyl)-n-(4-chlorophenyl)-n,5-dimethyl-1,2-oxazole-4-carboxamide Chemical compound C=1C=C(Cl)C=CC=1N(C)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl IGRCWJPBLWGNPX-UHFFFAOYSA-N 0.000 description 1
- SADHVOSOZBAAGL-UHFFFAOYSA-N 3-(trifluoromethoxy)aniline Chemical compound NC1=CC=CC(OC(F)(F)F)=C1 SADHVOSOZBAAGL-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Abstract
The invention provides a benzofuran derivative, a preparation method and application thereof, and relates to the technical field of FXR agonists. In particular, the invention relates to a compound shown in a general formula (I) or pharmaceutically acceptable salt or solvate thereof, which is used for preparing FXR agonist and can be used for treating nonalcoholic steatohepatitis, and FXR receptor binding activity reaches or even exceeds that of the prior medicine obeticholic acid, EC 50 The value is lower than 100nM, which is helpful for reducing the administration dosage of patients, so as to reduce the incidence and degree of adverse reaction, thereby improving the defects of serious side effect and large administration dosage of the prior medicines such as obeticholic acid and the like to a certain extent.(Ⅰ)。
Description
Technical Field
The invention belongs to the technical field of FXR agonists, and particularly relates to a benzofuran derivative, a preparation method and application thereof.
Background
Nonalcoholic steatohepatitis (NASH) is a chronic, progressive liver disease characterized by liver cell steatosis, balloon-like changes, inflammation and fibrosis. The disease can lead to death of hepatocytes and liver fibrosis, which if not treated in time can further progress to cirrhosis and liver cancer. NASH has become the most common cause of chronic hepatitis and end-stage liver disease worldwide as prevalence of obesity, type 2 diabetes and metabolic syndrome increases. NASH is a key component of exacerbation in the spectrum of nonalcoholic fatty liver disease (NAFLD), about 25% of patients with nonalcoholic fatty liver disease (NAFLD) can progress to NASH, and 30% or more of NASH patients have a possibility of developing cirrhosis or hepatocellular carcinoma (HCC).
NASH generally affects those suffering from metabolic syndrome such as obesity, high cholesterol, diabetes, hypertension, etc. Furthermore, genetic, pharmaceutical, infectious and other factors may lead to the onset of NASH. Studies have also shown that the prevalence of NASH increases with age, particularly in people over 40 years old.
Treatment of NASH typically involves integrated intervention including weight loss, changes in dietary structure, increases physical activity, and control of blood glucose and cholesterol levels. Drug therapy may also be an option, and many drugs may be used to reduce inflammation and improve metabolic function. However, existing therapeutic approaches still present limitations and challenges, and no specific drug has been approved for NASH treatment to date. Liver transplantation may be the only treatment option for patients with impaired liver function.
FXR (farnesoid X receptor) agonist is a novel drug, which takes FXR agonism as an action mechanism. FXR is an endogenous receptor that is expressed more widely in the liver, gut and gall bladder and regulates many metabolic and immune responses. Recent studies have shown that FXR agonists can significantly reduce the occurrence of NASH-related complications. FXR activation can reduce portal hypertension of cirrhosis, repair of intestinal barrier and reduce intestinal bacterial translocation, so the use of FXR agonists will benefit both pre-cirrhosis and cirrhosis patients. FXR agonists play a number of roles in the liver, regulating cholic acid metabolism and synthesis, lowering blood glucose and triglyceride levels, by activating FXR. Furthermore, FXR agonists are also expected to be useful for treating hepatitis such as NASH because they reduce fat accumulation and fibrosis in the liver.
To date, a number of clinical trials based on FXR agonists have been carried out, showing that they can have a positive effect on NASH treatment. In particular, a recent clinical test result for Oxcarbazepine (OCA) shows that OCA is significantly effective in treating NASH.
Oxcarbazepine (OCA) is a bile acid drug that reduces excessive accumulation of fat by the liver by modulating bile acid synthesis and bile acid metabolic pathways in the liver. Its molecular structure is similar to that of natural bile acid, but has strong activity. OCA can inhibit liver fat retention and eliminate fatty liver. In addition, it can improve the number and function of liver cells, reduce inflammation and fibrosis of liver, etc. OCA has been approved by the FDA for the treatment of advanced primary cholangitis (PBC). Several clinical trial studies have also demonstrated the effectiveness of OCA in treating NASH. For example, a clinical trial showed that patients with moderate to severe NASH had reduced liver inflammation and fibrosis following OCA treatment.
However, OCA also suffers from a number of adverse effects including diarrhea, nausea, loss of appetite, etc. In addition, certain monitoring procedures are also followed during OCA use, as it may increase the risk of hepatocholangitis. Patients need to be thoroughly evaluated to determine if they are suitable for treatment prior to receiving OCA treatment. In addition, the clinical middle-low dose group of the medicine cannot achieve statistically significant distinction, the other end point is not achieved to relieve the fatty liver, the safety is a problem which is always paid attention to, 51% of patients in the high dose group have skin itch, 9% of patients are withdrawn from the test, and adverse reaction exposure such as unbalance of LDL and cardiovascular event is increased before.
EYP001 is a novel drug for treating NAFLD and NASH, which is a bile acid-like molecule that acts on TGR5 (TakedaGprotein-coupledreeptor 5) receptor in vivo. Studies have shown that EYP001 is capable of promoting glucose metabolism and lipid metabolism in the liver and has the effect of improving liver inflammation and fibrosis by activating the signaling pathway of TGR5 receptor. The study also shows that EYP001 has remarkable curative effects on NAFLD and NASH, but the problems of safety, drug metabolism, dosage and the like still need to be further studied.
EYP001 has been subjected to some early clinical trials, but is currently not fully clinical data concerning its safety and effectiveness. Future clinical trials are necessary to determine the status and mechanism of action of this novel drug in NAFLD and NASH treatments, leading to better treatment options for patients.
In summary, FXR agonists are a potential drug, and are expected to be important components in future NASH treatments. However, FXR agonists are currently under some controversy and may adversely affect liver function, thus requiring patient assessment and monitoring prior to use of these drugs. Furthermore, improper use of FXR agonists may also lead to some negative effects, such as diarrhea and cholestasis.
Therefore, it is necessary to develop a novel FXR agonist to exhibit a better therapeutic effect while reducing the dosage of the drug, aiming at the shortages of the existing FXR agonists.
Disclosure of Invention
The invention aims to provide a benzofuran derivative which is used for preparing a medicine for treating non-alcoholic steatohepatitis, has the advantages of low dosage and high binding activity with FXR receptor, and solves the problems of the existing FXR agonist.
In order to achieve the above object, the present invention provides the following technical solutions:
a benzofuran derivative or a pharmaceutically acceptable salt or solvate thereof, said compound having the structural formula (i):
(Ⅰ)
wherein R is 1 、R 2 Each independently selected from phenyl, azaphenyl, alkyl, cycloalkyl, alkoxy, oxacycloalkyl, phenyl substituted with one or more substituents, azaphenyl substituted with one or more substituents each independently selected from halogen, alkyl, cycloalkyl, haloalkyl, ester, alkoxy, fluoroalkoxy, nitrile;
L 1 is an azacyclic ring, L 2 Selected from sulfonyl or alkoxy.
Preferably, the azaphenyl group includes pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and s-triazinyl.
Preferably, R 1 Selected from phenyl, cycloalkyl, alkoxy, oxacycloalkyl, phenyl substituted with one or more substituents each independently selected from halogen, alkyl, cycloalkyl, fluoroalkyl, ester, alkoxy, fluoroalkoxy, nitrile.
Preferably, R 2 Selected from phenyl, phenyl substituted with one or more substituents each independently selected from halogen.
Preferably, L 1 Selected from the following structures:
。
preferably, the structural formula of the compound is shown as the following formula (II):
(Ⅱ)
wherein R is 2 Represents phenyl substituted by one or more substituents.
Preferably, the compound is selected from:
。
preferably, the benzofuran derivative is selected from one of the following compounds:
n- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1 r,5 s) -8- ((2, 6-dichlorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) benzofuran-2-carboxamide;
n- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1S, 4S) -5- ((2, 6-dichlorophenyl) sulfonyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) benzofuran-2-carboxamide;
4- ((1 r,5 s) -8- ((3-chloro-2-fluorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide;
n- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1R, 5S) -8- ((3-chloro-4-fluorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) benzofuran-2-carboxamide.
The invention also provides a preparation method of the compound (II), which comprises the following steps:
step one, mixing 2-bromo-6-hydroxybenzaldehyde and K 2 CO 3 Placing the mixture in a reaction tube, adding a proper amount of N, N-dimethylformamide, then adding ethyl bromoacetate, reacting at normal temperature, detecting the disappearance of 2-bromo-6-hydroxybenzaldehyde by a dot plate, then heating the mixture at 140 ℃ for reaction for 3 hours, standing the reaction solution at-4 ℃ to separate out solids, filtering, washing filter residues with water, and drying to obtain 4-bromobenzofuran-2-carboxylic acid ethyl ester;
dissolving 4-bromobenzofuran-2-carboxylic acid ethyl ester and sodium hydroxide in methanol at room temperature, stirring at normal temperature for reaction for 1 hour, adding water equivalent to the methanol, adjusting the pH to 1-2, carrying out suction filtration, washing filter residues with water, and drying to obtain 4-bromobenzofuran-2-carboxylic acid;
step three, at room temperature, placing 4-bromobenzofuran-2-formic acid, 4-chloro-3-trifluoromethyl aniline, HATU and N, N-diisopropylethylamine in tetrahydrofuran, reacting for 12 hours at normal temperature, extracting with dichloromethane and water after the reaction is completed, merging organic phases, and performing column chromatography to obtain 4-bromo-N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide;
step four:
at room temperature, 4-bromo-N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide is reacted with compound (III), pd (OAc) 2 、BINAP、CS 2 CO 3 And a proper amount of 1, 4-dioxane is placed in a reaction tube, oil bath heating reaction is carried out at 120 ℃, spot plate detection is carried out, after 4-bromo-N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide disappears, the reaction solution is subjected to diatomite, and the filtrate is subjected to column chromatography dry sample loading to obtain a compound (IV);
step five:
placing the compound (IV) in a reaction tube at room temperature, adding dichloromethane, adding hydrogen chloride-dioxane solution, stirring at normal temperature, adjusting the pH to 8-10 after the reaction is completed, filtering, and drying filter residues to obtain a compound (V);
step six:
and (3) placing the compound (V), the compound (VI), the ultra-dry dichloromethane and the triethylamine in a reaction tube at room temperature, reacting for 3 hours at normal temperature, and performing column chromatography to obtain the compound (II).
The invention also provides application of any of the compounds or pharmaceutically acceptable salts or solvates thereof in preparing FXR agonists.
The beneficial effects are that:
the benzofuran derivative provided by the invention has better binding activity to FXR receptor and EC 50 The value is equal to or better than that of obeticholic acid, the minimum value can be lower than 100nM, and the preparation method canCan exhibit an agonistic effect on FXR at lower doses of administration.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention. Wherein:
FIG. 1 is a scheme showing the preparation of benzofuran derivatives according to example 1 of the present invention.
FIG. 2 is a scheme showing the preparation of benzofuran derivatives according to example 7 of the present invention.
FIG. 3 shows the general formula of benzofuran derivatives according to the present invention.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which are derived by a person skilled in the art based on the embodiments of the invention, fall within the scope of protection of the invention.
The present invention will be described in detail with reference to examples. It should be noted that, without conflict, the embodiments of the present invention and features of the embodiments may be combined with each other.
Aiming at the problems of large dosage, high incidence of side effects and no obvious treatment effect at low dosage of the existing FXR agonist, the invention provides a benzofuran derivative, which has the structure shown in the following formula (I):
(Ⅰ)
wherein R is 1 、R 2 Each independently selected from phenyl, azaphenyl, alkyl, cycloalkyl, alkoxy, oxacycloalkyl, phenyl substituted with one or more substituents, azaphenyl substituted with one or more substituents, each independently selected from halogen, alkyl, cycloalkyl, haloalkyl, halo,Ester groups, alkoxy groups, fluoroalkoxy groups, nitrile groups;
L 1 is an azacyclic ring, L 2 Selected from sulfonyl or alkoxy.
In a preferred embodiment of the present invention, the aforementioned azaphenyl groups include pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and s-triazinyl.
In a preferred embodiment of the invention, R 1 Selected from phenyl, cycloalkyl, alkoxy, oxacycloalkyl, phenyl substituted with one or more substituents each independently selected from halogen, alkyl, cycloalkyl, fluoroalkyl, ester, alkoxy, fluoroalkoxy, nitrile.
In a preferred embodiment of the invention, R 2 Selected from phenyl, phenyl substituted with one or more substituents each independently selected from halogen. In a preferred embodiment of the invention, L 1 Selected from the following structures:
。
the benzofuran derivatives, the preparation method and the application thereof are described in detail by specific examples.
Example 1
Preparation of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) -N- (3-methoxyphenyl) benzofuran-2-carboxamide:
the preparation route is shown in fig. 1, and specifically comprises the following steps:
step one, synthesizing 4-bromobenzofuran-2-carboxylic acid ethyl ester:
2-bromo-6-hydroxybenzaldehyde (1 eq) and K at room temperature 2 CO 3 (4 eq) is placed in a reaction tube, proper N, N-dimethylformamide is added, then ethyl bromoacetate (4 eq) is added for normal temperature reaction, a point plate detects that 2-bromo-6-hydroxybenzaldehyde disappears, then the reaction is heated at 140 ℃ for 3 hours, the solid is separated out after the reaction liquid is placed in a refrigerator at-4 ℃, the solid is collected by filtration, then washed by water and dried, and the target product is obtained as white solid with the yield of 67.8 percent, the purity of 89.6 percent and the MS m/z (ESI) of 270.09[ M+1]]。
Step two, synthesis of 4- (2- (ethoxycarbonyl) benzofuran-4-yl) piperazine-1-carboxylic acid tert-butyl ester:
at room temperature, 4-bromobenzofuran-2-carboxylic acid ethyl ester (1 eq), piperazine-1-carboxylic acid tert-butyl ester (1.2 eq), pd (OAc) 2 (0.1eq)、BINAP(0.1eq)、CS 2 CO 3 (2 eq) and proper amount of 1, 4-dioxane are placed in a reaction tube, oil bath heating reaction is carried out at 120 ℃, spot plate detection is carried out until 4-bromobenzofuran-2-carboxylic acid ethyl ester disappears, the reaction liquid is filtered through kieselguhr to obtain filtrate, and a column chromatography dry method is adopted to obtain white solid, the yield is 52.9%, the purity is 87.3%, and MSm/z (ESI) is 375.44[ M+1]]。
Step three, synthesizing 4- (piperazine-1-yl) benzofuran-2-ethyl formate:
at room temperature, tert-butyl 4- (2- (ethoxycarbonyl) benzofuran-4-yl) piperazine-1-carboxylate is placed in a reaction tube, dichloromethane is then added, 4mol/L hydrogen chloride-dioxane solution is then added, stirring is performed at room temperature, after the reaction is completed, sodium hydroxide is dropwise added until the pH value is 8-10, the solid is filtered and dried, and the target product is obtained as a white solid with the yield of 81.6% and the purity of 89.6%, MSm/z (ESI) of 275.32[ M+1].
Step four, synthesis of ethyl 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylate:
at room temperature, ethyl 4- (piperazin-1-yl) benzofuran-2-carboxylate 1 eq) and 2, 6-dichlorobenzenesulfonyl chloride (1.5 eq), an appropriate amount of ultra-dry dichloromethane, and triethylamine (5 eq) were placed in a reaction tube and reacted for 3 hours at room temperature, and column chromatography was performed to give a white solid in a yield of 72.1%, purity of 92.1%, MSm/z (ESI) of 484.36[ M+1].
Step five, synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid:
4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazine-1-yl) benzofuran-2-carboxylic acid ethyl ester (1 eq) and sodium hydroxide (4 eq) are dissolved in methanol at room temperature, stirred at room temperature for reaction for 1 hour, water which is equal to that of the methanol is added, 31% hydrochloric acid solution is added dropwise until the pH value reaches 1-2, the solid is filtered by suction, and the product is obtained by washing with water, wherein the yield is 56.9%, the purity is 91.5%, and MSm/z (ESI): 456.31[ M+1].
Step six, synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) -N- (3-methoxyphenyl) benzofuran-2-carboxamide:
4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid (1 eq), 3-methoxyaniline (1.2 eq), HATU (2 eq), N-diisopropylethylamine (DIPEA, 3 eq) were placed in tetrahydrofuran at room temperature and reacted for 12 hours at room temperature. After the reaction was completed, extraction was performed with dichloromethane and water, the organic phases were combined, and finally the target compound was obtained as a white solid by column chromatography, with a yield of 61.8%, a purity of 94.8%, and MSm/z (ESI): 561.45[ m+1], and NMR characterization results were as follows:
1 H NMR(400MHz，CDCl 3 )，δ8.26(d，J=25.5Hz，1H)，7.52(dd，J=19.1，11.3Hz，4H)，7.40-7.27(m，3H)，7.19(dd，J=15.9，8.2Hz，2H)，6.73(d，J=7.8Hz，2H)，3.84(d，J=9.6Hz，3H)，3.65(s，4H)，3.30(s，4H)。
example 2
Preparation of N- (3-cyanophenyl) -4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxamide:
the preparation route is as follows:
step one, the synthesis of 4-bromobenzofuran-2-carboxylic acid ethyl ester is completed in the same step one of the embodiment;
step two, the synthesis of the 4- (2- (ethoxycarbonyl) benzofuran-4-yl) piperazine-1-carboxylic acid tert-butyl ester is completed in the step two in the embodiment one;
step three, the synthesis of 4- (piperazine-1-yl) benzofuran-2-ethyl formate is completed in the same step three in the embodiment one;
step four, the synthesis of the ethyl 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylate is completed in the same step four in the first embodiment;
step five, the synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid is completed in the same step five of example one;
step six, synthesis of N- (3-cyanophenyl) -4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxamide:
4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid (1 eq), 3-aminobenzonitrile (1.2 eq), HATU (2 eq), N-diisopropylethylamine (DIPEA, 3 eq) were placed in tetrahydrofuran at room temperature and reacted for 12 hours at room temperature. After the reaction was completed, the target compound was obtained by extraction with methylene chloride and water, and the organic phases were combined and finally subjected to column chromatography as a white solid with a yield of 62.8%, purity of 95.3%, MSm/z (ESI): 556.43[ M+1], and the NMR characterization results were as follows:
1 H NMR(400MHz，CDCl 3 )，δ8.39(s，1H)，8.12(d，J=15.7Hz，1H)，7.91(d，J=7.9Hz，1H)，7.61(s，1H)，7.55~7.43(m，4H)，7.38(q，J=7.4Hz，2H)，7.22(d，J=8.3Hz，1H)，6.73(t，J=11.4Hz，1H)，3.60(d，J=46.5Hz，4H)，3.31(s，4H)。
example 3
Preparation of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) -N- (3- (1, 1-difluoroethoxy) phenyl) benzofuran-2-carboxamide:
the preparation route is as follows:
step one: the synthesis of 4-bromobenzofuran-2-carboxylic acid ethyl ester is completed in the first step of the embodiment;
step two: step two of the first example is performed to complete the synthesis of the tert-butyl 4- (2- (ethoxycarbonyl) benzofuran-4-yl) piperazine-1-carboxylate;
step three: step three of example one, the synthesis of 4- (piperazin-1-yl) benzofuran-2-carboxylic acid ethyl ester is completed;
step four: step four of example one was followed to complete the synthesis of ethyl 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylate;
step five: step five of example one was followed to complete the synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid;
step six: synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) -N- (3- (1, 1-difluoroethoxy) phenyl) benzofuran-2-carboxamide:
4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid (1 eq), 3-trifluoromethoxy aniline (1.2 eq), HATU (2 eq), N-diisopropylethylamine (DIPEA, 3 eq) were placed in tetrahydrofuran at room temperature and reacted for 12 hours at room temperature. After the reaction was completed, extraction was performed with dichloromethane and water, the organic phases were combined, and finally the target compound was obtained as a white solid by column chromatography, with a yield of 65.8%, a purity of 96.4%, and MSm/z (ESI): 615.42[ m+1], and the NMR characterization results were as follows:
1 H NMR(400MHz，CDCl 3 )，δ8.35(s，1H)，7.75(s，1H)，7.57(d，J=15.6Hz，2H)，7.52(d，J=7.9Hz，2H)，7.44~7.32(m，3H)，7.22(d，J=8.3Hz，1H)，7.03(t，J=10.0Hz，1H)，6.74(d，J=7.8Hz，1H)，3.69(d，J=24.7Hz，4H)，3.31(s，4H)。
example 4
Preparation of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) -N- (3, 5-dimethylphenyl) benzofuran-2-carboxamide:
the preparation route is as follows:
step one: the synthesis of 4-bromobenzofuran-2-carboxylic acid ethyl ester is completed in the first step of the embodiment;
step two: step two of the first example is performed to complete the synthesis of the tert-butyl 4- (2- (ethoxycarbonyl) benzofuran-4-yl) piperazine-1-carboxylate;
step three: step three of example one, the synthesis of 4- (piperazin-1-yl) benzofuran-2-carboxylic acid ethyl ester is completed;
step four: step four of example one was followed to complete the synthesis of ethyl 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylate;
step five: step five of example one was followed to complete the synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid;
step six: synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) -N- (3, 5-dimethylphenyl) benzofuran-2-carboxamide:
4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid (1 eq), 3, 5-dimethylaniline (1.2 eq), HATU (2 eq), N-diisopropylethylamine (DIPEA, 3 eq) were placed in tetrahydrofuran at room temperature and reacted for 12 hours at room temperature. After the reaction was completed, extraction was performed with dichloromethane and water, and the organic phases were combined, and finally the target compound was obtained as a white solid by column chromatography, with a yield of 61.2%, a purity of 94.1%, and MSm/z (ESI): 559.47[ m+1], and the NMR characterization results were as follows:
1 H NMR(400MHz，CDCl 3 )，δ8.22(s，1H)，7.57~7.44(m，3H)，7.40~7.30(m，4H)，7.23~7.14(m，1H)，6.82(s，1H)，6.73(d，J=7.8Hz，1H)，3.61(t，J=23.2Hz，4H)，3.30(s，4H)，2.34(s，6H)。
example 5
Preparation of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) -N- (4-methoxy-3-methylphenyl) benzofuran-2-carboxamide:
the preparation route is as follows:
step one: the synthesis of 4-bromobenzofuran-2-carboxylic acid ethyl ester is completed in the first step of the embodiment;
step two: step two of the first example is performed to complete the synthesis of the tert-butyl 4- (2- (ethoxycarbonyl) benzofuran-4-yl) piperazine-1-carboxylate;
step three: step three of example one, the synthesis of 4- (piperazin-1-yl) benzofuran-2-carboxylic acid ethyl ester is completed;
step four: step four of example one was followed to complete the synthesis of ethyl 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylate;
step five: step five of example one was followed to complete the synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid;
step six: synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) -N- (4-methoxy-3-methylphenyl) benzofuran-2-carboxamide:
4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid (1 eq), 4-methoxy-3-methylaniline (1.2 eq), HATU (2 eq), N-diisopropylethylamine (DIPEA, 3 eq) were placed in tetrahydrofuran at room temperature and reacted for 12 hours at room temperature. After the reaction was completed, dichloromethane and water were used for extraction, and the organic phases were combined, and finally the target compound was obtained by column chromatography as a white solid with a yield of 64.2%, a purity of 94.9%, and MSm/z (ESI): 575.47[ m+1], and the NMR characterization results were as follows:
1 H NMR(400MHz，CDCl 3 )，δ8.26(d，J=25.5Hz，1H)，7.52(dd，J=19.1，11.3Hz，4H)，7.40–7.27(m，3H)，7.19(dd，J=15.9，8.2Hz，2H)，6.73(d，J=7.8Hz，2H)，3.84(d，J=9.6Hz，3H)，3.65(s，4H)，3.30(s，4H)，2.25(s，3H)。
example 6
Preparation of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) -N- (4-methoxyphenyl) benzofuran-2-carboxamide:
the preparation route is as follows:
step one: the synthesis of 4-bromobenzofuran-2-carboxylic acid ethyl ester is completed in the first step of the embodiment;
step two: step two of the first example is performed to complete the synthesis of the tert-butyl 4- (2- (ethoxycarbonyl) benzofuran-4-yl) piperazine-1-carboxylate;
step three: step three of example one, the synthesis of 4- (piperazin-1-yl) benzofuran-2-carboxylic acid ethyl ester is completed;
step four: step four of example one was followed to complete the synthesis of ethyl 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylate;
step five: step five of example one was followed to complete the synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid;
step six: synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) -N- (4-methoxyphenyl) benzofuran-2-carboxamide:
4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid (1 eq), 4-methoxy-3-methylaniline (1.2 eq), HATU (2 eq), N-diisopropylethylamine (DIPEA, 3 eq) were placed in tetrahydrofuran at room temperature and reacted for 12 hours at room temperature. After the reaction was completed, extraction was performed with dichloromethane and water, the organic phases were combined, and finally the target compound was obtained as a white solid by column chromatography, with a yield of 61.3%, a purity of 92.7%, and MSm/z (ESI): 561.45[ m+1], and NMR characterization results were as follows:
1 H NMR(400MHz，CDCl 3 )，δ8.23(s，1H)，7.60(t，J=11.8Hz，2H)，7.56–7.47(m，3H)，7.35(dd，J=14.3，7.4Hz，2H)，7.20(d，J=8.3Hz，1H)，6.93(d，J=8.1Hz，2H)，6.72(d，J=7.8Hz，1H)，3.82(s，3H)，3.65(s，4H)，3.30(s，4H)。
example 7
Preparation of N- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1 r,5 s) -8- ((2, 6-dichlorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) benzofuran-2-carboxamide:
the preparation route is as follows:
step one: the synthesis of 4-bromobenzofuran-2-carboxylic acid ethyl ester is completed in the first step of the embodiment;
step two: synthesis of 4-bromobenzofuran-2-carboxylic acid:
at room temperature, 4-bromobenzofuran-2-carboxylic acid ethyl ester (1 eq) and sodium hydroxide (4 eq) are dissolved in methanol, stirred at normal temperature for reaction for 1 hour, water which is equal to methanol is added, 31% hydrochloric acid solution is added dropwise until the pH is 1-2, the solid is filtered by suction and washed with water to obtain the product, the yield is 80.4%, the purity is 91.5%, and MSm/z (ESI) is 242.04[ M+1].
Step three: synthesis of 4-bromo-N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide:
4-bromobenzofuran-2-carboxylic acid (1 eq), 4-chloro-3-trifluoromethylaniline (1.2 eq), HATU (2 eq), N-diisopropylethylamine (DIPEA, 3 eq) were placed in tetrahydrofuran at room temperature and reacted for 12 hours at room temperature. After the reaction was completed, extraction was performed with dichloromethane and water, and the organic phases were combined, and finally the target compound was obtained by column chromatography as a white solid with a yield of 59.4%, a purity of 92.4%, and MSm/z (ESI): 419.59[ M+1].
Step four: synthesis of (1R, 5S) -3- (2- ((4-chloro-3- (trifluoromethyl) phenyl) carbamoyl) benzofuran-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester:
4-bromo-N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide (1 eq) and (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1.2 eq), pd (OAc) 2 (0.1 eq), BINAP (0.1 eq), CS2CO3 (2 eq) and an appropriate amount of 1, 4-dioxane were placed in a reaction tube at room temperature and heated in an oil bath at 120℃to react, and spot-plating was detected until 4-bromo-N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide disappeared. The reaction solution was passed through celite to obtain a filtrate. The white solid is obtained by column chromatography dry sample loading, the yield is 52.9 percent, and the purity is 87.3 percent. MSm/z (ESI) 550.98[ M+1].
Step five: synthesis of 4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide:
at room temperature, (1R, 5S) -3- (2- ((4-chloro-3- (trifluoromethyl) phenyl) carbamoyl) benzofuran-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester is placed in a reaction tube, dichloromethane is then added, 4mol/L hydrogen chloride-dioxane solution is then added, stirring is carried out at normal temperature, after the reaction is completed, sodium hydroxide is dropwise added until the pH value is 8-10, the solid is filtered and dried, the target product is obtained as a white solid, the yield is 85.1 percent, the purity is 87.7 percent, and MSm/z (ESI) is 450.86[ M+1].
Step six: synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1R, 5S) -8- ((2, 6-dichlorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) benzofuran-2-carboxamide:
4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-3-yl) -N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide (1 eq) and 2, 6-dichlorobenzenesulfonyl chloride (1.5 eq), an appropriate amount of ultra-dry dichloromethane, triethylamine (5 eq) were placed in a reaction tube at room temperature and reacted for 3 hours at room temperature to give a white solid by column chromatography in 72.1% yield, 92.1% purity, MSm/z (ESI): 659.90[ M+1], NMR characterization results were as follows:
1 H NMR(400MHz，CDCl 3 )，δ8.53–8.32(m，1H)，8.01(d，J=17.2Hz，1H)，7.93(t，J=11.2Hz，1H)，7.60(s，1H)，7.54–7.44(m，3H)，7.34(t，J=8.1Hz，2H)，7.12(t，J=12.5Hz，1H)，6.65(d，J=7.9Hz，1H)，4.51(d，J=36.5Hz，2H)，3.47(d，J=11.2Hz，2H)，3.19(t，J=17.7Hz，2H)，2.17–1.92(m，4H)。
example 8
Preparation of N- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1S, 4S) -5- ((2, 6-dichlorophenyl) sulfonyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) benzofuran-2-carboxamide:
the preparation route is as follows:
step one: the synthesis of 4-bromobenzofuran-2-carboxylic acid ethyl ester is completed in the step one in the seventh embodiment;
step two: step two of the seventh example is performed to complete the synthesis of tert-butyl 4- (2- (ethoxycarbonyl) benzofuran-4-yl) piperazine-1-carboxylate;
step three: step three of example seven, the synthesis of 4- (piperazin-1-yl) benzofuran-2-carboxylic acid ethyl ester was completed;
step four: synthesis of tert-butyl (1R, 4R) -5- (2- ((4-chloro-3- (trifluoromethyl) phenyl) carbamoyl) benzofuran-4-yl) -2-azabicyclo [2.2.1] heptane-2-carboxylate:
4-bromo-N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide (1 eq), (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (1.2 eq), pd (OAc) 2 (0.1 eq), BINAP (0.1 eq), CS2CO3 (2 eq) and an appropriate amount of 1, 4-dioxane were placed in a reaction tube at room temperature and heated in an oil bath at 120℃to react, and the spot-on plate was examined, until 4-bromo-N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide disappeared. The reaction solution was passed through celite to obtain a filtrate. Dry column chromatography gives a white solid in 53.8% yield, 82.6% purity, MSm/z (ESI): 535.96[ M+1].
Step five: synthesis of 4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide:
(1R, 4R) -5- (2- ((4-chloro-3- (trifluoromethyl) phenyl) carbamoyl) benzofuran-4-yl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester is placed in a reaction tube at room temperature, dichloromethane is then added, 4mol/L hydrogen chloride-dioxane solution is then added, stirring is carried out at room temperature, after the reaction is completed, sodium hydroxide is added dropwise to pH=8-10, the solid is filtered and dried to obtain the target product as a white solid with a yield of 82.5% and a purity of 87.1% and MSm/z (ESI) of 435.83[ M+1].
Step six: synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1S, 4S) -5- ((2, 6-dichlorophenyl) sulfonyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) benzofuran-2-carboxamide:
4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-3-yl) -N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide (1 eq), 2, 6-dichlorobenzenesulfonyl chloride (1.5 eq), an appropriate amount of ultra-dry dichloromethane and triethylamine (5 eq) were placed in a reaction tube at room temperature and reacted for 3 hours at room temperature, and column chromatography gave a white solid in 72.1% yield, 92.1% purity, MSm/z (ESI): 645.87[ M+1], NMR characterization results were as follows:
1 H NMR(400MHz，CDCl 3 )，δ8.36(s，1H)，8.02(s，1H)，7.94(d，J=8.7Hz，1H)，7.62(s，1H)，7.51(t，J=8.2Hz，1H)，7.43(d，J=7.9Hz，2H)，7.29(dd，J=14.8，6.7Hz，2H)，6.94(d，J=8.2Hz，1H)，6.35(d，J=7.9Hz，1H)，4.83(s，1H)，4.65(d，J=12.8Hz，1H)，3.95(d，J=8.9Hz，1H)，3.79(t，J=9.3Hz，1H)，3.70(t，J=11.3Hz，1H)，3.65(d，J=9.1Hz，1H)，2.16(t，J=11.1Hz，1H)，2.09–1.98(m，1H)。
example 9
Preparation of 4- ((1 r,5 s) -8- ((3-chloro-2-fluorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide:
the preparation route is as follows:
step one: the synthesis of 4-bromobenzofuran-2-carboxylic acid ethyl ester is completed in the step one in the seventh embodiment;
step two: step two of the seventh example is performed to complete the synthesis of tert-butyl 4- (2- (ethoxycarbonyl) benzofuran-4-yl) piperazine-1-carboxylate;
step three: step three of example seven, the synthesis of 4- (piperazin-1-yl) benzofuran-2-carboxylic acid ethyl ester was completed;
step four: step four of example seven was followed to complete the synthesis of ethyl 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylate;
step five: step five of example seven was followed to complete the synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid;
step six: synthesis of 4- ((1R, 5S) -8- ((3-chloro-2-fluorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide:
4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-3-yl) -N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide (1 eq) and 3-chloro-2-fluorobenzenesulfonyl chloride (1.5 eq), an appropriate amount of ultra-dry dichloromethane, triethylamine (5 eq) were placed in a reaction tube at room temperature and reacted for 3 hours, column chromatography gave a white solid, yield 78.5%, purity 93.1%, MSm/z (ESI): 643.45[ M+1], NMR characterization results were as follows:
1 H NMR(400MHz，CDCl 3 )，δ8.40(s，1H)，8.03(s，1H)，7.95(d，J=8.7Hz，1H)，7.85(t，J=6.9Hz，1H)，7.63(dd，J=13.8，6.6Hz，1H)，7.60(s，1H)，7.53(d，J=8.6Hz，1H)，7.36(t，J=7.8Hz，1H)，7.25~7.18(m，1H)，7.17(d，J=8.4Hz，1H)，6.71(t，J=15.8Hz，1H)，4.48(s，2H)，3.49(d，J=11.3Hz，2H)，3.22(d，J=11.2Hz，2H)，2.03(t，J=26.3Hz，2H)，1.90(s，2H)。
example 10
Preparation of N- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1 r,5 s) -8- ((3-chloro-4-fluorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) benzofuran-2-carboxamide:
step one: the synthesis of 4-bromobenzofuran-2-carboxylic acid ethyl ester is completed in the step one in the seventh embodiment;
step two: step two of the seventh example is performed to complete the synthesis of tert-butyl 4- (2- (ethoxycarbonyl) benzofuran-4-yl) piperazine-1-carboxylate;
step three: step three of example seven, the synthesis of 4- (piperazin-1-yl) benzofuran-2-carboxylic acid ethyl ester was completed;
step four: step four of example seven was followed to complete the synthesis of ethyl 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylate;
step five: step five of example seven was followed to complete the synthesis of 4- (4- ((2, 6-dichlorophenyl) sulfonyl) piperazin-1-yl) benzofuran-2-carboxylic acid;
step six: synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1R, 5S) -8- ((3-chloro-4-fluorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) benzofuran-2-carboxamide:
4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-3-yl) -N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide (1 eq), 3-chloro-4-fluorobenzenesulfonyl chloride (1.5 eq), an appropriate amount of ultra-dry dichloromethane and triethylamine (5 eq) were placed in a reaction tube at room temperature and reacted for 3 hours at room temperature, column chromatography gave a white solid with 77.3% yield, 94.5% purity, MSm/z (ESI): 643.45[ M+1], NMR characterization results were as follows:
1 H NMR(400MHz，CDCl 3 )，δ8.40(s，1H)，8.01(d，J=11.5Hz，2H)，7.95(d，J=8.6Hz，1H)，7.82(s，1H)，7.57(d，J=11.3Hz，1H)，7.53(d，J=8.7Hz，1H)，7.33(dt，J=22.7，8.3Hz，2H)，7.17(d，J=8.3Hz，1H)，6.70(t，J=15.2Hz，1H)，4.31(d，J=39.5Hz，2H)，3.47(d，J=11.2Hz，2H)，3.21(d，J=11.2Hz，2H)，1.97(t，J=29.2Hz，2H)，1.68(d，J=44.8Hz，2H)。
FXR receptor binding activity assay:
the experimental steps are as follows:
(1) Preparing FXR-LBD of 2xGST label/Eu mixed solution of anti-GST to required volume, wherein the concentration of GST-FXR-LBD is 6nM, and Eu is 50 nl/hole;
(2) Preparing a 2x biotin-labeled SRC 1/streptomycin-allophycocyanin (SA-APC) mixture to a required volume, wherein the concentration of SRC1 is 1000nM and the concentration of streptomycin-allophycocyanin is 50 nl/well;
(3) Mixing two mixed solutions of 2xGST-FXR/Eu and SRC1/SA-APC in a ratio of 1:1;
(4) Mu.l of a mixture of GST-FXR/Eu and SRC1/SA-APC was added to a 384-well plate containing the test compound;
(5) Centrifuging at 1000rpm for 1min, and incubating at room temperature for 180min;
(6) Time-resolved fluorescence detection: the EnVision reader reads the board;
(7) Analysis of results: a. a value at 665nm divided by a value at 615 nm; excitation rate= (X-Min)/(Max-Min) ×100%, X representing 665/615 value for each concentration; min represents 665/615 without compound; max stands for 665/615 values for reference compounds.
+:EC 50 :500-1000nM，++:EC 50 :100-500nM，+++:EC 50 :<100nM。
It can be seen that the examplesThe EC50 value of the compound prepared in examples 7 was comparable to that of obeticholic acid 50 The value is superior to that of obeticholic acid, and when the compound is used for preparing FXR agonists, the administration dosage of patients is expected to be reduced, so that the effect of reducing the incidence and severity of adverse reactions is achieved.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A benzofuran derivative or a pharmaceutically acceptable salt thereof, wherein the benzofuran derivative has the structural formula (i):
(Ⅰ)，
wherein R is 1 、R 2 Each independently selected from phenyl, phenyl substituted with one or more substituents each independently selected from halogen;
L 1 selected from the following structures:
，
L 2 is sulfonyl.
2. A benzofuran derivative or a pharmaceutically acceptable salt thereof, wherein the benzofuran derivative has a structural formula represented by formula (ii):
(Ⅱ)，
wherein L is 1 Selected from the following structures:
，
R 2 represents phenyl substituted by one or more substituents each independently selected from halogen.
3. A benzofuran derivative or a pharmaceutically acceptable salt thereof, wherein said benzofuran derivative is selected from the group consisting of:
。
4. a benzofuran derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein said benzofuran derivative is selected from one of the following compounds:
n- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1 r,5 s) -8- ((2, 6-dichlorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) benzofuran-2-carboxamide;
n- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1S, 4S) -5- ((2, 6-dichlorophenyl) sulfonyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) benzofuran-2-carboxamide;
4- ((1 r,5 s) -8- ((3-chloro-2-fluorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide;
n- (4-chloro-3- (trifluoromethyl) phenyl) -4- ((1R, 5S) -8- ((3-chloro-4-fluorophenyl) sulfonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) benzofuran-2-carboxamide.
5. A process for the preparation of benzofuran derivatives according to claim 2, comprising the steps of:
step one, mixing 2-bromo-6-hydroxybenzaldehyde and K 2 CO 3 Placing the mixture in a reaction tube, adding a proper amount of N, N-dimethylformamide, then adding ethyl bromoacetate, reacting at normal temperature, detecting the disappearance of 2-bromo-6-hydroxybenzaldehyde by a dot plate, then heating the mixture at 140 ℃ for reaction for 3 hours, standing the reaction solution at-4 ℃ to separate out solids, filtering, washing filter residues with water, and drying to obtain 4-bromobenzofuran-2-carboxylic acid ethyl ester;
dissolving 4-bromobenzofuran-2-carboxylic acid ethyl ester and sodium hydroxide in methanol at room temperature, stirring at normal temperature for reaction for 1 hour, adding water equivalent to the methanol, adjusting the pH to 1-2, carrying out suction filtration, washing filter residues with water, and drying to obtain 4-bromobenzofuran-2-carboxylic acid;
step three, at room temperature, placing 4-bromobenzofuran-2-formic acid, 4-chloro-3-trifluoromethyl aniline, HATU and N, N-diisopropylethylamine in tetrahydrofuran, reacting for 12 hours at normal temperature, extracting with dichloromethane and water after the reaction is completed, merging organic phases, and performing column chromatography to obtain 4-bromo-N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide;
step four:
，
at room temperature, 4-bromo-N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide is reacted with compound (III), pd (OAc) 2 、BINAP、CS 2 CO 3 And a proper amount of 1, 4-dioxane is placed in a reaction tube, oil bath heating reaction is carried out at 120 ℃, spot plate detection is carried out, after 4-bromo-N- (4-chloro-3- (trifluoromethyl) phenyl) benzofuran-2-carboxamide disappears, the reaction solution is subjected to diatomite, and the filtrate is subjected to column chromatography dry sample loading to obtain a compound (IV);
step five:
，
placing the compound (IV) in a reaction tube at room temperature, adding dichloromethane, adding hydrogen chloride-dioxane solution, stirring at normal temperature, adjusting the pH to 8-10 after the reaction is completed, filtering, and drying filter residues to obtain a compound (V);
step six:
，
and (3) placing the compound (V), the compound (VI), the ultra-dry dichloromethane and the triethylamine in a reaction tube at room temperature, reacting for 3 hours at normal temperature, and performing column chromatography to obtain the compound (II).
6. Use of a benzofuran derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 for the preparation of FXR agonists.
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